Kir6.1‐dependent K_ATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain‐of‐function

Abstract

Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the K ATP channel activator pinacidil. K ATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional K ATP channels as verified by electrophysiological techniques. r Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil. r Smooth muscle-specific expression of Kir6.1 gain-of-function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the K ATP inhibitor glibenclamide. In contrast, lymphatic endothelial-specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function. r The high sensitivity of LSM to K ATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain-of-function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic agent.

Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome

“…Thus, although overactivity of skeletal myocyte KATP channels might contribute to atrophy, ACE/Ang II/ATR1 signaling is also a known mediator of atrophy and sarcopenia in skeletal muscle [ 42 ] and a potential major driver of the muscle pathology. Similarly, fiber damage may result in fluid leakage into the extracellular space, but the nature of the observed fluid, combined with the demonstration that lymphatic contractility can be markedly reduced by KATP GOF in lymphatic smooth muscle [ 43 ], further suggests a non-skeletal myocyte, i.e., lymphatic smooth muscle [ 43 ], contributor to the edema that characterizes the CS muscles.…”

Effects of Elevated Downstream Pressure and the Role of Smooth Muscle Cell Coupling through Connexin45 on Lymphatic Pacemaking

“…Cx45 SM-KO mice in this and our previous study do not develop peripheral lymphedema during the 10–12-month time course over which we have observed them [ 7 ]. Nor does it develop in mice expressing gain-of-function K ATP channels in LMCs, which exhibit even greater lymphatic contractile dysfunction than shown here [ 24 ]. We hypothesize that both contractile impairment and a chronic gravitational load are likely needed to produce significantly, readily detectable peripheral lymphedema.…”

“…Populations of LMCs were sorted and purified from mouse lymphatic vessels by means of FACS as previously described [ 24 ]. Briefly, intact inguinal-axillary lymphatic vessels were isolated [ 22 ] from Smmhc-Cre;eGFP or Smmhc-Cre;ROSA26 mTmG mice and cleaned of adipose and connective tissue.…”

Linking lymphatic function to disease

“…In the current issue of The Journal of Physiology , work by Davis et al . (2020) provides an example of meeting this challenge by linking ATP sensitive smooth muscle specific potassium channel (K ATP ) dysfunction to Cantú syndrome, a rare disease associated with genetic mutation that alters potassium channel function and leads to lymphoedema. In the context of lymphatic function, the genetic mutation is considered to cause the potassium channels to be preferentially in the open state (Davis et al .…”

“…In the context of lymphatic function, the genetic mutation is considered to cause the potassium channels to be preferentially in the open state (Davis et al . 2020). The results by Davis et al .…”